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WO2007131365A1 - Traitement des troubles néoplasiques à l'aide d'une farnésyl dibenzodiazépinone administrée par infusion intraveineuse continue - Google Patents

Traitement des troubles néoplasiques à l'aide d'une farnésyl dibenzodiazépinone administrée par infusion intraveineuse continue Download PDF

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Publication number
WO2007131365A1
WO2007131365A1 PCT/CA2007/000886 CA2007000886W WO2007131365A1 WO 2007131365 A1 WO2007131365 A1 WO 2007131365A1 CA 2007000886 W CA2007000886 W CA 2007000886W WO 2007131365 A1 WO2007131365 A1 WO 2007131365A1
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Prior art keywords
cancer
formula
compound
neoplasm
formulated
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PCT/CA2007/000886
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English (en)
Inventor
Henriette Gourdeau
Maxime Ranger
François Berger
Bryan Simard
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Thallion Pharmaceuticals Inc.
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Publication of WO2007131365A1 publication Critical patent/WO2007131365A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention relates to compositions and methods for inhibiting growth and proliferation of a neoplastic cell, and methods of treating neoplasms in a mammal using the compound of Formula I or a pharmaceutically acceptable salt, prodrug thereof. More particularly, the invention relates to the use of the compound of Formula I as a continuous
  • Neoplasia occurs when normal body cells are changed, 20 proliferating without regard to normal cellular restraints, and invade and colonize areas of the body normally occupied by other cells. See B. Alberts et al., Molecular Biology of the Cell 1255-1294 (3d ed. 1994). According to the American Cancer Society, one-half of American men and one-third of American women will at some point in their lives develop a 25 neoplastic disorder.
  • Abnormal cell proliferation is usually characterized by an increase rate of division and in some cases uncontrolled growth.
  • a proliferative cell disorder is a tumor or neoplasm.
  • primary malignant neoplasms are 30 particularly problematic given their tendency to invade surrounding tissues and metastasize to distant organs in the body.
  • the most frequently used methods for treating neoplasia include surgical procedures, radiation therapy, and drug therapies, and combinations of the foregoing. These methods involve significant risk (e.g., of infection, death) to the patient.
  • the probability of eliminating all malignant cells is small, particularly if the zone of the malignant growth is not well defined or if the primary tumor has metastasized by the time of surgery. Achieving therapeutic doses effective for treating neoplasm is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue.
  • An ideal anti-cancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells.
  • novel cancer therapeutics which have higher efficacy, specificity, or reduced side effects.
  • the compound of Formula I (see below) was disclosed in CA 2,466,340, incorporated by reference in its entirety, and was shown to possess a broad spectrum of anticancer activity by in vitro testing. Both this application and a poster presentation (poster 569, 16 th EORTC-NCI- AACR Symposium - Geneva, Sept. 28 to Oct. 1 , 2004) disclosed in vivo activity following intraperitoneal administration in glioma mouse models, as well as PK and toxicity profiles including intravenous (IV) bolus, intraperitoneal (IP) and oral (PO) administration. Following the toxicity profile, the AACR poster suggested IV bolus dosing to be the preferred route of administration. The compound was further disclosed in Charan et al. (2004), J. Nat. Prod., vol 67, 1431-1433 as an antimicrobial agent, and in lgarashi et al. (2005), J. Antibiot, vol 58, no 5, 350-352.
  • the invention provides a novel method for the administration of the compound of Formula I, or a pharmaceutically acceptable prodrug of the compound of Formula I: comprising the step of administering by a continuous intravenous infusion, a therapeutically effective amount of the compound of Formula I to a patient in need thereof.
  • the continuous intravenous infusion is given for at least 8 hours per day, over a period of 1 to 28 days, preferably from 7 to 14 days.
  • the continuous intravenous infusion is given 24 hours per day over a period of 1 to 28 days, preferably from 7 to 14 days.
  • the invention provides a method of treating a neoplasm in a mammal, comprising the step of administering by continuous intravenous infusion to the mammal, a therapeutically effective amount of the compound of Formula I, or a pharmaceutically acceptable prodrug of the compound of Formula I 1 such that the neoplasm is treated.
  • the invention provides a method of inducing apoptosis of a neoplasm in a mammal, comprising the step of administering by continuous intravenous infusion to the mammal a therapeutically effective amount of the compound of Formula I 1 or a pharmaceutically acceptable prodrug, such that the neoplasm is treated or controlled.
  • the invention provides use of a continuous intravenous infusion dosage of the compound of Formula I, or a pharmaceutically acceptable prodrug thereof, for the inhibition of the growth or proliferation of a neoplastic cell in a mammal.
  • the invention provides use of a continuous intravenous infusion dosage of the compound of Formula I, or a pharmaceutically acceptable prodrug thereof, for inducing apoptosis in a neoplastic or cancer cell.
  • the invention provides use of a continuous intravenous infusion dosage of the compound of Formula I, or a pharmaceutically acceptable prodrug thereof, for the treatment of neoplasia in a mammal.
  • the invention provides use of the compound of Formula I 1 or a pharmaceutically acceptable prodrug thereof, in the preparation of a continuous intravenous infusion medicament for the treatment of neoplasia in a mammal.
  • the pharmaceutical composition for treating neoplasia comprises the compound of Formula I and at least one further therapeutic agent selected from the group consisting of chemotherapeutic agents, biological response modifiers, multidrug reversing agents and target specific antitumor agents.
  • this invention provides a commercial package, kit or system for continuous intravenous infusion, comprising a continuous intravenous infusion dosage of the compound of Formula I 1 or a pharmaceutically acceptable salt or prodrug thereof, together with instructions for use in the treatment of neoplasia in a mammal.
  • the infusion dosage is a concentrated form and the commercial package, kit or system further comprises a pre-filled syringe or other container containing an aqueous media for reconstitution of the infusion dosage.
  • the commercial package, kit or system further comprises an infusion bag.
  • the commercial package, kit or system further comprises connectors.
  • the commercial package, kit or system further comprises an administration set including a pump connector and anti- siphon valve.
  • the commercial package, kit or system further comprises an ambulatory infusion pump.
  • the cancer cell, neoplasm or pre-cancerous or cancerous condition, in the above-mentioned methods and uses is selected from leukemia, melanoma, breast cancer, lung cancer, pancreatic cancer, ovarian cancer, renal cancer, colon or colorectal cancer, prostate cancer, and CNS cancer.
  • the cancer cell, and pre-cancerous or cancerous condition in the above- mentioned methods and uses, is selected from leukemia, breast cancer, prostate cancer, and CNS cancer.
  • the compound of Formula I for continuous intravenous infusion is formulated to be administered over a period of at least 8 hours per day, at a dosage of about 0.5 to about 150 mg/kg per day over a period of about 1 day to about 28 days.
  • the dosage is about 0.5 to about 100 mg/kg per day, or about 1.0 to about 50 mg/kg per day.
  • the continuous intravenous infusion is administered 24 hours per day, over a period of about 7 days to about 14 days. Most preferably, the dosage is about 30 to 500 mg/m 2 of body surface area, per day.
  • Figure 1 shows in vivo antitumor activity of Formula I against the rat glioma (C6) tumor xenograft in female athymic (nu/nu) nude mice when given IP at 20 mg/kg (days 6-13) followed by 10 mg/kg (days 14-18) (upside down triangle), SC at 30 mg/kg (days 6-13) followed by 15 mg/kg (days 14-18) (square), and IV at 100 mg/kg (days 6-10 and days 13-17) (triangle), compared to the vehicle control group (circle) given IP at 5 ml_/kg (days 6-18). Treatment was initiated when tumors were palpable (day 6).
  • Figure 2 shows the survival of mice xenografted with orthotopic C6 glioma tumor, treated daily with vehicle (squares) or the compound of Formula I (circles). Daily treatment with the compound of Formula I led to an increase survival of 7 days resulting in a 29% increase in life span.
  • Figure 3 shows tumor volume growth curves of the different groups (mean ⁇ SEM) from in vivo antitumor activity of Formula I against the human glioma (U-87MG) tumor xenograft. Treatment was initiated when tumors were palpable (day 24).
  • Formula I (30 mg/kg) (square) and drug-free control vehicle (5 mL/kg) (circle) were given SC once daily (Monday to Friday) for 2 weeks (q1d x 5) 2 wk.
  • Temodozolimide (diamond- shaped), used as positive control, was given PO at 150 mg/g every four days (total of 3 treatments).
  • Figure 4 shows tumor volumes of all the animals from the different treatment groups of the in vivo activity assay of Figure 3, when compared at day 34, after which time animals from the control group had to be sacrificed due to tumor burden.
  • Figure 5 shows the mean ( ⁇ SD) plasma concentrations of the compound of Formula I in Swiss mice following 30 mg/kg bolus intravenous (IV), bolus intraperitoneal (IP), subcutaneous (SC) and oral (PO) administrations.
  • Figure 6 shows the mean concentration of the compound of Formula I in various tissues, 30 minutes after 30mg/kg intravenous (IV), intraperitoneal (IP) and subcutaneous (SC) bolus administrations.
  • Figure 7 shows the antitumor efficacy of the compound of Formula I against human prostate tumor (PC3) xenografts in male Harlan nude mice.
  • Figure 8 shows the antitumor efficacy of the compound of Formula I against human prostate tumor (PC3) xenografts on individual male Harlan nude mice at day 22 of treatment.
  • Figure 9 shows the antitumor efficacy of the compound of Formula I against human breast tumor (MDA-MB-231) xenografts in female Harlan nude mice.
  • Figure 10 shows the antitumor efficacy of the compound of Formula I against human breast tumor (MDA-MB-231) xenografts on individual female Harlan nude mice at day 21 of treatment.
  • Figure 11 shows the mean ( ⁇ SD) plasma concentrations, during and post-infusion, of the compound of Formula I in Sprague-Dawley rats when administered continuous intravenous infusion (CIV) for 14 days (336 hours) at a dosage of 25 mg/kg/day, 50 mg/kg/day, and 75 mg/kg/day .
  • CIV continuous intravenous infusion
  • Figure 12 shows the mean ( ⁇ SD) plasma concentrations, during and post-infusion, of the compound of Formula I in Cynomolgus monkeys when administered CIV for 14 days (336 hours) at a dosage of 5 mg/kg/day, 15 mg/kg/day, and 30 mg/kg/day.
  • Figure 13 shows a simulated Formula I plasma concentration-time profiles in humans, following a CIV infusion at 30 mg/m 2 /day for 14 days.
  • the present invention also provides methods for treating a neoplastic disorder in a mammal.
  • the methods comprise administering a therapeutically effective amount of the compound of Formula I by continuous intravenous infusion, or pharmaceutically acceptable prodrug thereof to a mammal in need of treatment.
  • the present invention also provides pharmaceutical compositions comprising the compound of Formula I for use in continuous intravenous infusion and its pharmaceutically acceptable prodrugs.
  • the invention relates to a farnesyl dibenzodiazepinone having the chemical structure represented by Formula I below:
  • the "compound of Formula I" or simply "Formula I", "active ingredient” or “drug”, or equivalent expressions used herein, may be described as a dibenzodiazepinone having a farnesyl substituent located on the nitrogen atom in the 10 position of the ditjenzodiazepine ring (i.e., the amide nitrogen in the diazepinone ring), and three phenolic hydroxy substituents in the 4,6 and 8 positions of the dibenzodiazepinone ring, namely 10-farnesyl-4,6,8-trihydroxy-dibenzodiazepin-11-one.
  • the term also includes pharmaceutically acceptable prodrugs thereof.
  • pharmaceutically acceptable prodrug means any pharmaceutically acceptable ester, salt of an ester or any other derivative of a farnesyl dibenzodiazepinone, which upon administration to a mammal is capable of providing, either directly or indirectly, a compound of formula I or a biologically active metabolite or residue thereof.
  • Particularly favored salts or prodrugs are those with improved properties, such as solubility, efficacy, or bioavailability of the compounds of this invention when such compounds are administered to the mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Exemplary prodrugs of the compound of Formula I include compounds wherein one or more of the 4, 6 and 8-hydroxy groups is bounded to any group that, when administered to a mammalian subject, is cleaved to form the free hydroxyl group.
  • Examples of prodrugs include, but are not limited to, acetate, formate, hemisuccinate, benzoate, dimethylaminoacetate and phosphoryloxycarbonyl derivatives of hydroxy functional groups; dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters or carboxyalkyl esters of hydroxy functional groups. Carbamate and carbonate derivatives of the hydroxy groups are also included.
  • Derivatizations of hydroxyl groups also encompassed, are (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group is an alkyl group optionally substituted with groups including, but not limited to, ether, amino and carboxylic acid functionalities, or where the acyl group is an amino acid ester.
  • phosphate and phosphonate ' esters, sulfate esters, sulfonate esters which are in alkylated (such as bis- pivaloyloxymethyl (POM) phosphate triester) or in the salt form (such as sodium phosphate ester (-P(O)O ' 2 Na + 2 )).
  • prodrugs used in anticancer therapy and their metabolism see Rooseboom et a/ (2004), Phamacol. Rev., vol 56, 53-102.
  • the prodrug may also be prepared as its pharmaceutically acceptable salt.
  • compositions Comprising a Farnesyl Dibenzodiazepinone
  • the farnesyl dibenzodiazepinone may be formulated into a pharmaceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising the farnesyl dibenzodiazepinone is useful for treating diseases and disorders associated with uncontrolled cellular growth and proliferation, such as a neoplastic condition.
  • the pharmaceutical composition comprising the farnesyl dibenzodiazepinone may be packaged into a convenient commercial package providing the necessary materials, such as the pharmaceutical composition and written instructions for its use in treating a neoplastic condition, in a suitable container.
  • the compounds of the present invention are formulated for continuous intravenous (CIV) infusion administration for the therapeutic or prophylactic treatment of neoplastic and proliferative diseases and disorders.
  • CIV continuous intravenous
  • Any known device useful for infusion of drug formulations can be used to effect such administration.
  • the compound can be mixed with conventional pharmaceutical carriers and excipients and used in the form of a solution.
  • the administrable compositions comprising a compound of the present invention will contain from about 0.01% to about 30%, about 0.05% to about 25%, about 0.05% to about 15%, about 0.1 % to about 10% or about 0.1% to about 5% by weight of the active compound.
  • compositions disclosed herein are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent, or eliminate cancer.
  • cancer See, e.g., Gennaro AR (ed), Remington's Pharmaceutical Sciences, 2000, Mack Publishing Company, Easton, PA; and Goodman and Gilman, Pharmaceutical Basis of Therapeutics, 2001 , Pergamon Press, New York, NY, the contents of which are incorporated herein by reference, for a general description of the methods for administering various agents for human therapy).
  • the term "unit dosage" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of famesyl dibenzodiazepinone calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable carriers.
  • the unit dosage contains from about 10 to about 1000 mg of active ingredient, per m 2 of body surface of the subject, per day. In another embodiment, the unit dosage contains from about 20 to about 750 mg of active ingredient, per m 2 of body surface of the subject, per day. In another embodiment, the unit dosage.contains from about 30 to about 500 mg of active ingredient, per m 2 of body surface of the subject, per day.
  • the unit dosage may be compounded for several days, for example, for the administration of a dose of 30 mg/m 2 /day over a 7-day period, the unit dosage includes at least 378 mg of active ingredient, for a human subject of 1.8 m 2 of body surface area.
  • the unit dosage for a 7-day infusion may contain from about 300 mg to 10 000 mg of active ingredient.
  • compositions of the present invention comprise the compound of the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and/or excipients, collectively referred to herein as "carrier” materials, and if desired other active ingredients.
  • Pharmaceutically acceptable carriers include, for example, solvents, vehicles or medium such as saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (e.g., Tween-80TM or Crillet 4 HPTM), polyethylene glycol) 300 and 400 (PEG 300 and 400), PEGylated castor oil (E.g.
  • Cremophor EL poloxamer 407 and 188
  • hydrophobic carriers include, for example, fat emulsions, lipids, PEGylated phospholipids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes. The term specifically excludes cell culture medium.
  • Excipients or additives included in a formulation have different purposes depending, for example on the nature of the drug, and the mode of administration.
  • examples of generally used excipients include, without limitation: stabilizing agents, solubilizing agents and surfactants, buffers, antioxidants and preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending or viscosity agents, inert diluents, antibacterials, chelating agents, administration aids, and combinations thereof.
  • the compositions may contain common carriers and excipients, such as, but not limited to, sodium citrate, citric acid, sodium chloride, mannitol, glucose, ascorbic acid, sodium ascorbate.
  • Formulations for CIV administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions, suspensions or fat emulsions, comprising a compound of this invention, or a pharmaceutically acceptable prodrug thereof.
  • the CIV form used for injection must be fluid to the extent that easy syringability exists.
  • These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules.
  • the compounds can be dissolved in a carrier such as a solvent or vehicle, for example, polyethylene glycol, propylene glycol, ethanol, corn oil, benzyl alcohol, glycofurol, N, N- dimethylacetamide, ⁇ /-methylpyrrolidone, glycerine, saline, dextrose, water, glycerol, hydrophobic carriers, and combinations thereof.
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • a carrier such as a solvent or vehicle
  • stabilizing agents e.g. carbohydrates, amino acids and polysorbates
  • solubilizing agents e.g.
  • cetrimide sodium docusate, glyceryl monooleate, polyvinylpyrolidone (PVP) and polyethylene glycol (PEG)) and surfactants (e.g. polysorbates, tocopherol PEG succinate, poloxamer and CremophorTM), buffers (e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like), antioxidants and preservatives (e.g.
  • BHA, BHT, gentisic acids such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol), chelating agents, and administration aids (e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vasoconstrictors for prolongation and agents that increase tissue permeability), and combinations thereof.
  • agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like
  • tonicity agents for adjusting physiological compatibility
  • suspending or viscosity agents e.g. thimersol, benzethonium chloride, benzalkon
  • CIV formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes.
  • Fat emulsions include in addition to the above- mentioned excipients, a lipid and an aqueous phase, and additives such as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose).
  • emulsifiers e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil
  • osmotic agents e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose.
  • Liposomes include natural or derived phospholipids and optionally stabilizing agents such as cholesterol.
  • the parenteral unit dosage form of the compound can be a ready-to-use solution of the compound or a salt thereof in a suitable carrier in sterile, hermetically sealed ampoules or in sterile pre-loaded syringes, or containers suitable for use with an infusion pump, e.g. infusion bags.
  • the suitable carrier optionally comprises any of the above-mentioned excipients.
  • the unit dosage for of the compound of the present invention can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.
  • powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants.
  • a sterile formulation of the compound of Formula I and optionally one or more additives, including solubilizers or surfactants, can be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion.
  • Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5% glucose or dextrose or Ringer'sTM solution.
  • the invention relates to a method for inhibiting growth and/or proliferation of cancer cells in a mammal.
  • the invention provides a method for treating neoplasms in a mammal.
  • Mammals include ungulates (e.g. sheeps, goats, cows, horses, pigs), and non-ungulates, including rodents, felines, canines and primates (i.e. human and non-human primates).
  • the mammal is a human.
  • neoplasm As used herein, the terms “neoplasm”, “neoplastic disorder”, “neoplasia” “cancer,” “tumor” and “proliferative disorder” refer to cells having the capacity for autonomous growth, i.e., an abnormal state of condition characterized by rapidly proliferating cell growth which generally forms a distinct mass that show partial or total lack of structural organization and functional coordination with normal tissue.
  • the terms are meant to encompass hematopoietic neoplasms (e.g. lymphomas or leukemias) as well as solid neoplasms (e.g.
  • Hematopoietic neoplasms are malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) and components of the immune system, including leukemias (related to leukocytes (white blood cells) and their precursors in the blood and bone marrow) arising from myeloid, lymphoid or erythroid lineages, and lymphomas (relates to lymphocytes).
  • Solid neoplasms include sarcomas, which are malignant neoplasms that originate from connective tissues such as muscle, cartilage, blood vessels, fibrous tissue, fat or bone.
  • Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures (including external epithelia (e.g., skin and linings of the gastrointestinal tract, lungs, and cervix), and internal epithelia that line various glands (e.g., breast, pancreas, thyroid).
  • neoplasms that are particularly susceptible to treatment by the methods of the invention include leukemia, and hepatocellular cancers, sarcoma, vascular endothelial cancers, breast careers, central nervous system cancers (e.g. astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma and glioblastoma), prostate cancers, lung and bronchus cancers, larynx cancers, esophagus cancers, colon cancers, colorectal cancers, gastro-intestinal cancers, melanomas, ovarian and endometrial cancer, renal and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid), and pancreatic cancer.
  • leukemia and hepatocellular cancers
  • sarcoma vascular endothelial cancers
  • breast careers central nervous system cancers (e.g. astrocytoma, gliosarcoma, neuroblastoma, oli
  • the farnesyl dibenzodiazepinone is brought into contact with or introduced into a cancerous cell or tissue.
  • the methods of the invention for delivering the compositions of the invention in vivo utilize art- recognized protocols for delivering therapeutic agents with the only substantial procedural modification being the substitution of the farnesyl dibenzodiazepinone of the present invention for the therapeutic agent in the art-recognized protocols.
  • the route by which the farnesyl dibenzodiazepinone is administered, as well as the formulation, carrier or vehicle will depend on the location as well as the type of the neoplasm. A wide variety of administration routes can be employed.
  • the farnesyl dibenzodiazepinone may be administered by intravenous or intraperitoneal infusion or injection.
  • the farnesyl dibenzodiazepinone may be administered by injection directly into the neoplasm.
  • the farnesyl dibenzodiazepinone may be administered intravenously or intravascularly.
  • the farnesyl dibenzodiazepinone may be administered in a manner such that it can be transported systemically through the body of the mammal and thereby reach the neoplasm and distant metastases for example intrathecally, intravenously, intraventricular ⁇ , intramuscularly or orally.
  • the farnesyl dibenzodiazepinone can also be administered subcutaneously, intraperitoneal ⁇ , topically (for example for melanoma), rectally (for
  • example colorectal neoplasm vaginally (for example for cervical or vaginal neoplasm), nasally or by inhalation spray (for example for lung neoplasm).
  • a continuous infusion may also be given intraventricular ⁇ , intraarterially (e.g. infusion through hepatic artery for liver cancer), intracavitary (e.g. intraperitoneal for ovarian cancer), or intravesical ⁇ (e.g. to treat bladder cancer).
  • the preferred route of administration of the present invention is by continuous intravenous infusion.
  • the farnesyl dibenzodiazepinone is administered in an amount that is sufficient to inhibit the growth or proliferation of a neoplastic cell, or to treat a neoplastic disorder.
  • the term "inhibition” refers to suppression, killing, stasis, or destruction of cancer cells.
  • the inhibition of mammalian cancer cell growth according to this method can be monitored in several ways. Cancer cells grown in vitro can be treated with the compound and monitored for growth or death relative to the same cells cultured in the absence of the compound.
  • a cessation of growth or a slowing of the growth rate i.e., the doubling rate
  • a slowing of the growth rate i.e., the doubling rate
  • a slowing of the growth rate e.g., by 50% or more at 100 micromolar
  • cancer cell inhibition can be monitored by administering the compound to an animal model of the cancer of interest.
  • animal model of the cancer of interest examples of experimental non-human animal cancer models are known in the art and described below and in the examples herein.
  • a cessation of tumor growth (i.e., no further increase in size) or a reduction in tumor size (i.e., tumor volume by least a 58%) in animals treated with the compound relative to tumors in control animals not treated with the compound is indicative of significant tumor growth inhibition (see Anticancer Drug Development Guide: preclinical screening, clinical trials and approval; B.A. Teicher and P.A. Andrews, ed., 2004, Humana Press, Totowa, NJ).
  • treatment refers to the application or administration of a farnesyl dibenzodiazepinone to a mammal, or application or administration of a farnesyl dibenzodiazepinone to an isolated tissue or cell line from a mammal, who has a neoplastic disorder, a symptom of a neoplastic disorder or a predisposition toward a neoplastic disorder, with the purpose to cure, heal, alleviate, relieve, alter, ameliorate, improve, or control the disorder, the symptoms of disorder, or the predisposition toward disorder.
  • treating is defined as administering, to a mammal, an amount of a farnesyl dibenzodiazepinone sufficient to result in the prevention, reduction or elimination of neoplastic cells in a mammal ("therapeutically effective amount").
  • the therapeutically effective amount and timing of dosage will be determined on an individual basis and may be based, at least in part, on consideration such as the age, body weight, sex, diet and general health of the recipient subject, on the nature and severity of the disease condition, and on previous treatments and other diseases present. Other factors also include the duration of administration, drug combination, the tolerance of the recipient subject to the compound and the type of neoplasm or proliferative disorder.
  • a therapeutically effective amount of the compound is in the range of about 0.5 to about 150 mg/kg of body weight of the mammal per day, about 0.5 to about 100 mg/kg body weight per day, or about 1 to about 50 mg/kg body weight per day.
  • the therapeutically effective doses of the above embodiments may also be expressed in milligrams per square meter (mg/m 2 ), e.g. in the case of a human patient.
  • a therapeutically effective amount of the compound is in the range of about 10mg to about 1000 mg of active ingredient per m 2 of body surface of the subject, per day, from about 20 mg to about 750 mg of active ingredient per m 2 of body surface of the subject, per day, from about 30 mg to about 500 mg of active ingredient, per m 2 of body surface of the subject, per day, or from about 120 mg to about 480 mg of active ingredient, per m 2 of body surface of the subject, per day.
  • Conversion factors for different mammalian species may be found in Freireich et al, Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man, Cancer Chemoth. Report, 1966, 50(4): 219-244).
  • tumor size and/or tumor morphology is measured before and after initiation of the treatment, and treatment is considered effective if either the tumor size ceases further growth, or if the tumor is reduced in size, e.g., by at least 10% or more (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100%, that is, the absence of the tumor).
  • Prolongation of survival, time-to-disease progression, partial response and objective response rate are surrogate measures of clinical activity of the investigational agent.
  • Tumor shrinkage is considered to be one treatment- specific response. This system is limited by the requirement that patients have visceral masses that are amenable to accurate measurement.
  • Methods of determining the size of a tumor in vivo vary with the type of tumor, and include, for example, various imaging techniques well known to those in the medical imaging or oncology fields (MRI, CAT, PET, etc.), as well as histological techniques and flow cytometry.
  • evaluation of serum tumor markers are also used to evaluate response (eg prostate-specific antigen (PSA) for prostate cancer, and carcino-embryonic antigen (CEA), for colon cancer).
  • PSA prostate-specific antigen
  • CEA carcino-embryonic antigen
  • Other methods of monitoring cancer growth include cell counts (e.g. in leukemias) in blood or relief in bone pain (e.g. prostate cancer).
  • the dosage unit is compounded for delivery over several days, e.g., using , an intravenous infusion of the farnesyl dibenzodiazepinone compound over a several day period.
  • the dosage unit contains a corresponding multiple of the daily dose.
  • the effective dose is administered as an infusion, e.g. over a period of about 8 hours to about 24 hours per day.
  • the compound may be administered as a treatment, for up to 30 days.
  • the effective dose is administered as a continuous intravenous (CIV) infusion over 24 hours, for a period of about 1 to about 30 days, preferably for a period of about 7 to about 14 days.
  • CIV continuous intravenous
  • treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments.
  • the treatment can be administered as a 24 hours CIV infusion, for a duration of 28 days, repeated four times, with a resting period between each treatment.
  • Another example includes 14-day treatments separated by 7-day resting periods.
  • the farnesyl dibenzodiazepinone may be administered in conjunction with or in addition to known anticancer compounds or chemotherapeutic agents.
  • agents include, but are not limited to, 5- flurouracil, mitomycin C, methotrexate, hydroxyurea, nitrosoureas (e.g., BCNU, CCNU), cyclophosphamide, dacarbazine, thiotepa, atreptozocine, temozolomide, enzastaurin, erlotinib, mitoxantrone, anthracyclins (Epirubicin and Doxurubicin), etopside, pregnasome, platinum compounds such as carboplatin and cisplatin, taxanes such as paclitaxel and docetaxel; hormone therapies such as tamoxifen and anti-estrogens; antibodies to receptors, such as herceptin and Iressa; aromatase inhibitors, progestational agents and
  • Toxicity and therapeutic efficacy of farnesyl dibenzodiazepinone compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. Therapeutic efficacy is determined in animal models as described above and in the examples herein. Toxicity studies are done to determine the lethal dose for 10% of tested animals (LD10). Animals are treated at the maximum tolerated dose (MTD): the highest dose not producing mortality or greater than 20% body weight loss.
  • the effective dose (ED) is related to the MTD in a given tumor model to determine the therapeutic index of the compound.
  • a therapeutic index (MTD/ED) close to 1.0 has been found to be acceptable for some chemotherapeutic drugs, a preferred therapeutic index for classical chemotherapeutic drugs is 1.25 or higher.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of compositions of the invention will generally be within a range of circulating concentrations that include the MTD.
  • the dosage may vary within this range depending upon the dosage form employed and the schedule of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range of the compound. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • mice Animal models to determine antitumor efficacy of a compound are generally carried out in mice. Either murine tumor cells are inoculated subcutaneously into the hind flank of mice from the same species
  • SCID mice severe combined immune deficient mice
  • nude mice nude mice
  • the compound of Formula I was isolated from the fermentation broth of either strains of Micromonospora [S01]046 or 046-ECO11 respectively having IDAC 231203-01 and 070303-01 accession numbers (International Depository Authority of Canada (IDAC), Bureau of Microbiology, Health Canada, 1015 Arlington Street, Winnipeg, Manitoba, Canada, R3E 3R2).
  • IDAC International Depository Authority of Canada
  • Bureau of Microbiology Health Canada
  • 1015 Arlington Street Winnipeg, Manitoba, Canada
  • R3E 3R2 Research Institute of Canada
  • the compound of Formula I was produced and isolated as described in WO 2004/065591 in August 2004.
  • the structure of the compound of Formula I was identified as described in Canadian Patent application no. 2,507,567.
  • EXAMPLE 2 In Vivo Efficacy in C6 Glioma Models 1. In vivo efficacy in a C-6 glioblastoma model:
  • the rat C6 glioblastoma antitumor efficacy study was performed at INSERM U318 (Grenoble, France).
  • the rat C6 glioblastoma subcutaneous tumor model is based on the use of a rat C6 cell line obtained from a rat glial tumor induced by N-nitrosomethylurea (Benda et a/. (1968), Science, vol 161 , 370-371).
  • Formula I stock solutions 24 and 40 mg/mL in 20% ethanol, 20% PEG-400 and 60% Tween 80 were diluted with sterile 5% dextrose in water (D5W) to prepare dosing solutions of 6 mg/mL and 10 mg/mL of Formula I in a vehicle consisting of 5% ethanol, 5% PEG-400, 15% Tween-80, and 75% D5W.
  • D5W sterile 5% dextrose in water
  • Group 1 control group
  • Group 2 received drug-free vehicle (5% ethanol, 5% PEG-400, 15% Tween-80, and 75% D5W) IP (5 mL/kg), once daily on days 6-18 (q1d x 13).
  • Group 2 received Formula I (6 mg/mL) IP at 20 mg/kg, once daily on days 6 to 13 and then at 10 mg/kg once daily on days 14 to 18.
  • Group 3 received Formula I (6 mg/mL) SC at 30 mg/kg, once daily on days 6 to 13 and then at 15 mg/kg once daily on days 14 to 18.
  • Group 4 received Formula I (10 mg/mL) IV at 100 mg/kg q1d x 5 for 2 weeks.
  • TGI Tumor growth inhibition
  • T/C ⁇ 42%) is indicative of antitumor activity.
  • Statistical analysis was calculated by the two-tailed unpaired t test using the Prism software. Animals were weighed at least twice weekly during and after treatment until completion of the study. The mice were examined frequently for overt signs of any adverse drug-related side effects. Animals were euthanized if they showed more than 15% body weight loss for 3 consecutive days or 20% body weight loss during a single day. [0062] When the time to endpoint (TTE) for each mouse was also calculated by the following equation:
  • TTE Ioq10 (endpoint volume) - b m
  • % tumor growth delay % tumor growth delay
  • the compound of Formula I was administered following three different routes, SC, IP or IV, at different concentrations depending on the route of administration. Maximum body weight loss of 15% was observed on Day 13 for the IP group receiving 20 mg/kg (Q1 D x 8) followed by 10 mg/kg (Q1 D x 7) and 11% for the SC group receiving 30 mg/kg (Q1D x 8) followed by 15 mg/kg (Q1 D x 7). No significant body weight loss was observed for the IV group. The effect of the different treatment routes on tumor growth inhibition was analyzed at Day 18.
  • the compound of Formula I was administered intraperitoneal ⁇ (IP) at a concentration of 30 mg/kg (volume of 10 mL/Kg) on days 1 , 2 and 3 followed by IP injections of 10 mg/kg on days 4 and 5 and 9 to 38.
  • Vehicle (30% PEG; 30% PG; 40% H 2 O) was injected in a volume of 10 ml_/kg using the same route and schedule.
  • EXAMPLE 3 In vivo antitumor efficacy in a U-87MG glioma model
  • the human U-87 MG (ATCC ® no. HTB-14TM) glioblastoma antitumor efficacy study was performed at INSERM U318 (Grenoble, France).
  • the U-87MG cell line is derived from a brain glioblastoma of a 44-year-old Caucasian female.
  • Formula I stock solutions 24 and 40 mg/mL in 20% ethanol, 20% PEG-400 and 60% Tween 80 were diluted with sterile 5% dextrose in water (D5W) to prepare a dosing solution of 6 mg/mL of the compound of Formula I in a vehicle consisting of 5% ethanol, 5% PEG- 400, 15% Tween-80, and 75% D5W.
  • D5W sterile 5% dextrose in water
  • mice Female athymic (nu/nu) nude mice (6-7 weeks of age) were inoculated SC with 5 x 10 6 U-87MG cells (day 0). Tumor bearing animals were randomized (10 per group) when tumors were palpable (day 24).
  • Group 1 control group
  • drug-free vehicle 5% ethanol, 5% PEG-400, 15% Tween-80, and 75% D5W
  • SC 5 mL/kg
  • Group 2 received Formula I (6 mg/mL) SC at 30 mg/kg, q1d x 5 over 2 weeks (days 24-28 and 32-35).
  • Group 3 (positive control group) received temozolomide PO at 150 mg/kg, q4d x3. Each animal was euthanized when its tumor reached the predetermined endpoint size ( ⁇ 2,500 mm 3 ) or at the end of the study (D40). Tumor growth inhibition (TGI) was calculated on day 34 post tumor cell inoculation, at which time some animals from the vehicle control group had to be sacrificed due to tumor burden.
  • TGI Tumor growth inhibition
  • Formula I has demonstrated in vitro activity in this cell line with an IC 50 of 10.9 ⁇ M.
  • EXAMPLE 4 Pharmacokinetics
  • Plasma values of the compound of Formula I falling below the limit of quantitation (LOQ) were set to zero.
  • the following pharmacokinetic parameters were calculated: area under the plasma concentration versus time curve from time zero to the last measurable concentration time point (AUCO-t), area under the plasma concentration versus time curve extrapolated to infinity (AUCinf), maximum observed plasma concentration (Cmax), time of maximum plasma concentration (tmax), apparent first-order terminal elimination rate constant (kel), apparent first-order terminal elimination half-life will be calculated as 0.693/kel (ti /2 ).
  • the systemic clearance (CL) of the compound of Formula I after intravenous administration was calculated using Dose/AUCinf.
  • Pharmacokinetic parameters were calculated using KineticaTM 4.1.1 (InnaPhase Corporation, Philadelphia, PA).
  • Model [0074] The anticancer activity of the compound of Formula I was further tested in a murine P388 leukemia model in mice. f0075 "
  • PG propylene glycol
  • PEG 400 polyethylene glycol 400
  • mice DBA/2 female mice (6 weeks of age) were injected intraperitoneally (IP) with 1 x 10 6 P388 murine leukemia cells (day 0). Mice were randomized in 4 groups (10 mice per group) at Day 1 and treated with the following dose and schedule:
  • Group 1 IV injection of vehicle (PEG/PG formulation) on D1 and D8, daily IP administration of vehicle from D2 to D7 and from D9 to D10
  • Group 2 ivinjection of the compound of Formula I in PEG-PG formulation at 50 mg/kg on D1 followed by daily IP administration of the compound of Formula I in PEG-PG
  • PEG-PG formulation at 10 mg/kg from D1 to D4 and from D8 to D14
  • mice body weights were recorded twice a week. Lethality and behaviour of animals were recorded every day. All vehicle control mice died between D8 to D10 from peritoneal carcinomatosis associated with ascites. Three (3) mice from group 2 died one day after treatment due to formulation toxicity. The remaining seven (7) died between days 8 and 12. Mice from group 3 died between days 8 and 12. The results are expressed as percent of mean survival time of treated animals over the mean survival time of the control group (treated vs control, T/C%) and as increase life span (mean survival time of treated animals minus that of control animals over the mean survival time of the control group; ILS%). By NCI criteria, T/C exceeding 125% and ILS increasing 25% indicate that the drug has significant anticancer activity.
  • the anticancer activity of the compound of Formula I was further tested in a human PC3 prostate model in mice.
  • HRLN male nude mice (8 weeks of age) were implanted with 1 mm 3 PC3 tumor fragments subcutaneously (SC) in the right flank. Animals were randomized (ten per group) when tumors reach an average size of 80 - 120 mg and treatment began according to the table below.
  • the compound of Formula I was formulated in 5% ethanol, 5% PEG-400, 15% Polysorbate 80, and 75% of water containing 5% dextrose.
  • Tumor measurements were taken twice weekly using callipers and were converted to tumor mass (in milligrams) using the formula: with 2 (mm) x length (mm) x 0.52. Body weights were also recorded twice weekly. Statistical analysis was done using the unpaired two-tailed Student's t test.
  • %T/C was calculated at day 38 once animals in the control group had to be sacrificed due to tumor burden.
  • Bolus intravenous treatment did not result in activity (likely due to short half-life and lack of sustaining therapeutically effective drug levels).
  • bolus subcutaneous administration at 30 mg/kg given from days 1 to 5, 8 to 12 and 15 to 19, or at 50 mg/kg every three days x 7 (days 1 , 4, 7, 10, 13, 16 and 19) where we maintain drug levels at therapeutically effective drug concentrations for over 8 hours resulted in significant antitumor activity with %T/C of 25.5% and 14.6%, respectively (P ⁇ 0.0001).
  • Figure 7 shows antitumor efficacy results of the compound of Formula I against human prostate tumor xenografts.
  • Figure 8 shows antitumor efficacy results on individual animals on the 22 nd day of treatment.
  • EXAMPLE 7 Efficacy of Formula I against Human MDA-MB-231 Breast Cancer
  • the antitumor activity of the compound of Formula I was further tested in a human MD-MB-231 breast cancer model in mice.
  • HRLN female nude mice (8 weeks of age) were treated with 5x10 6 MDA-MB-231 tumor cells (SC) in the right flank. Animals were randomized (ten per group) when tumors reach an average size of 80 - 120 mg and treatment began according to the table below.
  • the compound of Formula I was formulated in 5% ethanol, 5% PEG-400, 15% Polysorbate 80, and 75% of water containing 5% dextrose.
  • Tumor measurements were taken twice weekly using calipers and were converted to tumor mass (in milligrams) using the formula: with 2 (mm) x length (mm) x 0.52. Body weights were also recorded twice weekly. Statistical analysis was done using the unpaired two-tailed Student's t test.
  • %T/C was calculated at day 21 once animals in the control group had to be sacrificed due to tumor burden.
  • Bolus intravenous treatment did not result in activity (likely due to short half-life and lack of sustaining therapeutically effective drug levels).
  • subcutaneous administration at 20 mg/kg given everyday for 21 days or at 30 mg/kg given from days 1 to 5, 8 to 12 resulted in significant antitumor activity with %T/Cs of 40% and 35% respectively; P ⁇ 0.0001).
  • Figure 9 shows antitumor efficacy results of the compound of Formula I against human breast tumor xenografts.
  • Figure 10 shows antitumor efficacy results on the 21 st day of treatment.
  • EXAMPLE 8 In Vivo CIV Administration of the Compound of Formula I [0087] Antitumor evaluation of the compound of Formula I against human tumors engrafted into nude mice indicated that antitumor efficacy was dependent on the route of administration. Indeed, while bolus intravenous (IV) administration was better tolerated and higher doses could be administered, it did not result in antitumor activity. On the other hand, subcutaneous (SC) and intraperitoneal (IP) bolus administrations, while not as well tolerated (IP dosing resulted in some intestinal occlusion and SC dosing in swelling and thickening of the skin), were effective. Maximum tolerated doses in mice for IV, SC and IP bolus administrations are 200 mg/kg, 30 mg/kg and 20 mg/kg, respectively. The pharmacokinetic profile of the compound of Formula I following these different administration routes was thus evaluated.
  • IV bolus intravenous
  • IP intraperitoneal
  • Neoplastic drugs administered by infusion are normally administered as short bolus infusions (30 min for up to 8h). Since preclinical evaluation of Formula I indicated that sustained and prolonged exposure (up to two weeks) is required for antitumor activity, and intraperitoneal and subcutaneous administrations are not suitable for anticancer treatment in humans, continuous intravenous infusion was evaluated for PK profile and toxicity in rats and monkeys. a) In vivo pharmacokinetics of Formula I given CIV in rats:
  • Sprague-Dawley rats received an intravenous continuous infusion over 14 days of Formula I at 25 mg/kg/day, 50 mg/kg/day, or 75 mg/kg/day at a rate of 2 ml_/kg/h for 14 consecutive days (same formulation as in Example 7).
  • Blood was collected from the jugular vein in tubes containing K 2 EDTA from 3 rats/sex/group at the following time points: 2, 6, and 12 hours after the start of dosing on Day 1 , on Day 2 at 6 hours (approximately 30 hours after the start of dosing), on Days 6 and 10 at 6 hours, and on Day 15, 1 hour prior the end of dosing, and then at 5 min, 15 min, 30 min, 1 h, and 2 h after the end of dosing.
  • Results from this 14-day IV continuous infusion of Formula I are shown in Table 4 and Figure 11.
  • steady-state Formula I plasma concentrations were observed throughout the 14-day CIV infusion, with steady-state plasma concentrations of 347 ng/mL (-0.8 ⁇ M) and 1 ,796 ng/mL (-3.9 ⁇ M), respectively.
  • Formula I plasma concentration was unusually high on Day 10 (1 ,753 ng/mL or -3.8 ⁇ M) and decreased back to the steady-state level at Day 14 as measured during prior measurements (1 ,150 ng/mL or -2.5 ⁇ M), suggesting possible analytical or biological variability.
  • the drug was infused intravenously (24 hours/day) into the femoral vein at a dose rate of 2 ml/kg/hour for 14 consecutive days.
  • Blood samples were removed from each monkey on Days 1 , 2, 6, 10, and 15 of the treatment period. Monkeys were bled by venipuncture and samples were collected into tubes containing K 2 EDTA. On Day 1 , samples were collected at 2, 6, and 12 hours after initiation of treatment. Additional samples were collected at 30 hours after the start of infusion (Day 2). On Days 6 and 10, samples were collected at approximately 6 hours after the bag changes.
  • Results from this 14-day IV continuous infusion of Formula I are shown in Table 5 and Figure 12.
  • steady-state Formula I plasma concentrations were observed throughout the 14-day CIV infusion, with mean steady-state plasma concentrations (between 30 h and 14 days) of 358 ng/mL (-0.8 ⁇ M) and 1 ,173 ng/mL (-2.5 ⁇ M), respectively.
  • Formula I plasma concentration increased throughout the 14-day infusion period from 2,814 ng/mL (-6.1 ⁇ M) at Day 1 to 4,354 ng/mL (-9.4 ⁇ M) at Day 6, to 6,855 ng/mL (-15 ⁇ M) by Day 10, and to 8,561 ng/mL (-18.5 ⁇ M) by day 15.
  • Plasma concentrations in the 15 mg/kg/day and the 30 mg/kg/day groups exceeded the therapeutic threshold observed in the in vivo antitumor activity experiments throughout the 14-day infusion period.
  • AUCs for the different groups increased approximately proportionally to the dose received between the low and middle dose groups, with a mean AUC of 119,018 ng/mL * h for the 5 mg/kg/day group, 400, 116 ng/mL*h for the 15 mg/kg/day group (3.4-fold increase between the groups, which is proportional to the 3-fold increase in dose level).
  • the AUC value for the high dose group (30 mg/kg/day) was markedly greater, i.e. 1 ,874,950 ng/mL * h, which is 4.7-fold higher than that of the middle dose group, despite the 2-fold increase in dose level.
  • the T 1/2 z for the compound of Formula I varied between 8.1 and 11.5 h for the different dosage groups.
  • Acute toxicity was also evaluated in a 24-hour CIV administration schedule in monkeys and doses of 35 mg/kg and 70 mg/kg, for a period of 24 hours (infusion rate of 2 mL/kg/hour), were both well tolerated.
  • Plasma concentrations of Formula I were obtained from mice, rats, and monkeys following intravenous injection or continuous infusion.
  • Formula I pharmacokinetic parameters in mice, rats, and monkeys were estimated using population pharmacokinetic analysis, a function of the software program NONMEMTM (version 5).
  • NONMEMTM version 5
  • Typical population pharmacokinetic parameters for Formula I in humans were extrapolated from allometric equations that were derived from pharmacokinetic parameters estimated in the three animal species.
  • Formula I plasma concentration-time profiles following 9-day or 14-day continuous infusion were simulated in a patient (weight, 70 kg; BSA, 1.8 m 2 ) with a typical population clearance (mean CL), 50% higher clearance (mean CL + 50% x mean CL), and 50% lower clearance (mean CL - 50% x mean CL), respectively.
  • a two-compartment model with a first-order elimination from the central compartment adequately described Formula I plasma concentration-time profiles following intravenous bolus injection (30 mg/kg) in mice and rats, 7-day continuous infusion in rats (50 to 170 mg/kg/day), and 14-day continuous infusion in monkeys (5 to 30 mg/kg/day).
  • the estimated population pharmacokinetic parameters of Formula I in mice, rats, and monkeys are presented in Table 6.
  • a 14-day continuous infusion in monkeys resulted in mean steady-state plasma concentrations of 0.75, 2.57, and 14.07 ⁇ M at dose levels of 5, 15, and 30 mg/kg/day, respectively, and corresponding mean clearance values of 0.63, 0.57, and 0.23 L/h/kg, respectively.
  • Application of a two-compartment model with Michaelis-Menten elimination better described the concentration data in monkeys than the linear model. Because the target concentration in humans is 2 ⁇ M, at which linear pharmacokinetics is assumed, all simulations for human plasma concentrations were performed based on a two-compartment model with linear first-order elimination.
  • Formula I concentrations were estimated for a patient (70 kg, BSA 1.8 rrrj with typical mean population pharmacokinetic parameters (CL, 0.236 L/h/kg; V1, 0.198 L/kg; V2, 0.559 L/kg; Q, 0.032 L/h/kg), a patient with 50% lower CL than the typical mean value (0.118 L/h/kg), and a patient with 50% higher CL than the typical mean value (0.354 L/h/kg).
  • CL mean population pharmacokinetic parameters
  • the compound of Formula I is administered to humans for the treatment of cancer.
  • the product is formulated (bulk formulation) as follows: Ingredient: % wt
  • the bulk formulation is reconstituted in sterile 0.9 saline prior to patient administration.
  • Bulk formulation vials are provided with a drug reconstitution kit consisting of a sterile 60 ml_ pre-filled syringe containing 52 ml_ of 0.9% saline, infusion bag, and administration set (with pump connector) and extension set.
  • the extension set comprises an anti- siphon valve and a sterile 0.2 micron in-line filter.
  • the vial content is diluted with 52 ml_ of sterile 0.9% saline with the aid of a pre-filled syringe.
  • the dosing formulation is then transferred to a 250-mL, 500-mL, or 1-L EVA or PP infusion bag.
  • the infusion bag is connected to a CADD Prizm VIP 6101 model pump for continuous 24-hour infusion.
  • the daily dose is adjusted with the flow rate of the pump, which is programmed and locked by the pharmacist. Patient is monitored for adverse side effects and efficacy of the treatment.
  • a 180 mg/m 2 daily dose is given during a period of 14 days to a human patient having a 1.8 m 2 body surface area.
  • the patient is administered daily volume of about 72.34 ml_ (324.1 mg of drug), for a total of 1012.8 ml_ (4537.4 mg of drug) of the reconstituted formulation above at a flow rate adjusted to about 3.014 mL/h.
  • the 14-day infusion is given in two 7-day infusions, i.e. changing infusion bag after 7 days, each bag administering a total volume of about 506.4 mL
  • the patient is then allowed to rest for 7 days.
  • One or more additional 14-day infusion treatments are given in the same manner, with or without adjustment of the dosage, depending on response and adverse side effects.

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Abstract

Cette invention concerne des procédés d'inhibition de la croissance et/ou de la prolifération d'une cellule néoplasique, et des procédés de traitement de néoplasmes par l'administration du composé dibenzodiazépinone farnésylée de Formule (I) par infusion intraveineuse continue. L'invention comprend des compositions pharmaceutiques comprenant le composé de Formule (I).
PCT/CA2007/000886 2006-05-16 2007-05-16 Traitement des troubles néoplasiques à l'aide d'une farnésyl dibenzodiazépinone administrée par infusion intraveineuse continue WO2007131365A1 (fr)

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